The current therapies for SLE are largely non-specific and empirical. Previous work in the human disease, as well as in several mouse models, has indicated that B cells play a central role in the pathogenesis. In the present proposal, the efficacy and mechanisms of anti-B cell therapy in the treatment of SLE will be investigated by parallel studies in a murine model for SLE (MRL/lpr); in humans, including the patients studied in the clinical protocol proposed in this application; and in a mouse/human model using SCID mice injected with human PBL. In Specific Aim 1, we will determine how we can deplete B cells from the peripheral lymphoid organs and how this will affect disease in the MRL/lpr mouse model. We will determine how B cells will recover, and how we can insure the maintenance of B-cell tolerance. In the human portion of the grant (Specific Aim 2 and Specific Aim 3) we will clarify the mechanisms of B-cell depletion with anti-CD20 therapy of humans with SLE, and what effect such depletion has on B cells and B-cell function in such patients. It is anticipated that the information obtained in these parallel studies will determine how B-cell depletion can be an effective therapy for existing SLE and will help us modify clinical protocols for B-cell depletion in SLE patients in conjunction with the proposed trials (Project 2, D. Albert, PI). This will permit a thorough evaluation of the therapeutic potential of this novel approach.